Emerging evidence suggests that idiopathic pulmonary fibrosis (IPF) results from epithelial injury and abnormal wound repair, with dysregulated epithelial-fibroblast crosstalk leading to epithelial apoptosis, matrix remodeling and progressive fibrosis. Our recent work suggests a novel paradigm in which myofibroblasts, key effector cells in matrix deposition and structural remodeling in IPF, may be derived from alveolar epithelial cells (AEC) through epithelial-mesenchymal transition (EMT). EMT can be viewed as an extreme form of cell plasticity characterized by loss of epithelial markers, cytoskeletal reorganization and transition to a spindle- shaped morphology concurrent with acquisition of mesenchymal markers. EMT has long been known to play a role in cellular transdifferentiation during development and tumor invasion. It is increasingly being recognized that, following epithelial stress/injury, epithelial cells can give rise to fibroblasts and thereby contribute to the pathogenesis of fibrosis by undergoing EMT. However, mechanisms underlying EMT in this context are poorly understood. Transforming growth factor (TGF-[unreadable]), implicated as a 'master switch' in induction of fibrosis, plays a pivotal role in EMT, and recent studies suggest a role for activation of the Wnt/[unreadable]-catenin pathway in AEC in IPF. A demonstrated role for [unreadable]-catenin signaling in EMT in the context of development and tumor progression, and the central role of TGF-[unreadable] in EMT and IPF, suggest that interactions between these two pathways may be a major factor mediating EMT in AEC. The overall goal of this proposal is to investigate molecular mechanisms underlying EMT in AEC, focusing on crosstalk between TGF-[unreadable] and Wnt/[unreadable]-catenin pathways. Our main hypotheses are that 1) EMT in AEC involves interactions between TGF-[unreadable] and Wnt/[unreadable]-catenin pathways, 2) TGF-[unreadable]-induced EMT in AEC is Smad-dependent and 3) modulation of EMT in AEC will provide new therapeutic approaches to management of patients with IPF. These hypotheses will be investigated by addressing the following Specific Aims: 1) Explore the role of Wnt/[unreadable]-catenin pathway in EMT in AEC; 2) Investigate Smad-dependence of TGF-[unreadable]-induced EMT in AEC; 3) Characterize interactions between Wnt/[unreadable]-catenin and TGF-[unreadable] pathways in mediating EMT in AEC; and, 4) Investigate effects of modulation of Wnt/[unreadable]-catenin pathway on EMT in AEC. We will utilize well-characterized in vitro models of AEC differentiation (in which phenotype can be experimentally modulated), established animal models of fibrosis and EMT, and lung tissue from patients with IPF to investigate the role of these interactions in EMT in AEC and its relevance to human disease. Understanding the precise molecular interactions that lead to EMT promises to lead to identification of novel therapeutic targets for pulmonary fibrosis that could inhibit progression of this devastating disease and provide new therapeutic options for management of patients with IPF. PUBLIC HEALTH RELEVANCE. Idiopathic pulmonary fibrosis (IPF) is a progressive disorder of unknown etiology with no effective treatment. We recently demonstrated that lung epithelial lining cells may themselves contribute to fibrosis by changing into fibroblasts through a process called epithelial-mesenchymal transition (EMT), suggesting that strategies for interrupting/preventing EMT could be of benefit in IPF. Understanding the molecules/signals that activate EMT should lead to development of novel strategies for treatment of IPF and other fibrotic lung disorders. [unreadable] [unreadable] [unreadable]